Short bowel syndrome (SBS) following massive bowel resection for various conditions, especially necrotizing entercolitis (NEC), is a devastating complication that affects neonates especially those delivered <36 weeks gestational age. These children are especially susceptible to recurrent blood stream infections (BSI), repeated hospital admissions and subsequent poor growth. All of these contribute to a very high burden on the primary caretakers and the health care system. Organisms associated with recurrent BSI in these children are predominantly gut related. However, there is still a lack of understanding of the intestinal microbial ecology of these children and whether it has a role in BSI, enteral feeds and ultimately growth. Glutamine (GLN) supplementation has been shown in adults with SBS to decrease mucosal damage, lower rates of BSI and associated sepsis and improve positive nitrogen balance. In children, there is currently insufficient data to determine whether enteral GLN supplementation improves clinical outcomes in young infants with significant gastrointestinal resection leading to SBS. The overall purpose of this pilot clinical study is to obtain needed preliminary data on the efficacy of enteral GLN supplementation in children with SBS as a result of significant intestinal resection due to NEC in the context of a rigorous, double-blind exploratory clinical trial with the following specific aims: Specific Aim 1: To perform a double-blind, randomized, placebo controlled, 6-months pilot study of enteral GLN (0.6g/kg) vs. isocaloric, isonitrogenous alanine (placebo) treatment in PN-dependent SBS children due to NEC to evaluate the efficacy of GLN to decrease BSI (primary endpoint) and serial serum concentrations of TNF- , IL1- 2, IL-6 and IL-8 (secondary endpoint). Specific Aim 2: To assess the efficacy of 6 months of therapy with enteral GLN on somatic growth parameters [length velocity (primary endpoint), weight velocity and head circumference] in Aim 1 subjects and the impact of BSI on these growth parameters. Specific Aim 3: To comprehensively assess the gut lumenal microbiome (using state-of-the art molecular methods) in Aim 1 SBS patients versus non-SBS, age-matched control subjects (primary endpoint), to correlate major bacterial dynamics present in the lumen with BSI due to specific microbes and to explore whether the gut lumenal microbiome is altered by enteral GLN treatment. This proposal will facilitate the development of a multicenter, multidisciplinary team from Emory University, University of Michigan and University of Colorado at Boulder to assess new methods for decreasing BSI and improving growth as well as to gain insights into the intestinal microbial ecology of SBS children. PUBLIC HEALTH RELEVANCE: Short bowel syndrome (SBS) is a devastating clinical problem affecting approximately 30,000 Americans who suffer from its complications and high cost of care. Current management strategies are not effective in preventing the complications or improving outcomes in SBS. This proposed trial will assess glutamine supplementation as a novel nutrient strategy to improve clinical outcomes in pediatric SBS and provide insight into the intestinal microbial ecology of SBS patients.